The present invention is concerned with new processes for the preparation of 2-(2-thienyl)-ethylamine and derivatives thereof having the following formula: ##STR2## wherein R.sub.1 and R.sub.2 are hydrogen or taken together form a phenyl ring. Some of the compounds of formula I have already been prepared according to a variety of methods including reduction of 2-.OMEGA.-nitrovinyl-thiophene with lithium aluminum hydride [S. Gronovitz & Sandberg, Arkiv. for Kemi, (1970), 32, 217; M. L. Dressler, M. Soullie, J. Het. Chem., (1970), 7, 1257]. They have also been prepared from 3-(2-thienyl)-propionamide, by means of a Hoffman degradation reaction [G. Barger, A. Easson, J. Chem. Soc., (1938), 2100]. Another method features reduction of 2-cyahomethyl thiophene with lithium aluminum hydride [B. F. Growe, F. F. Nord, J. Org. Chem., (1950), 15, 81; J. W. MacFarland, H. L. Howes, J. Med. Chem., (1969), 12, 1079]. These compounds have also been prepared by transamination of phthalimide derivatives as displayed in U.S. Pat. No. 4,128,561 to Braye. However, such prior methods either do not provide compounds of the formula (I) in sufficient yields, or require the use of dangerous or expensive chemicals, such as lithium aluminum hydride.
Consequently, the object of the present invention is to provide an inexpensive industrial synthesis process which will produce 2-(2-thienyl)-ethylamine and derivatives thereof of the aforementioned formula (I) in improved yields.
The subject compounds, 2-(2-thienyl)-ethylamine and derivatives thereof, are known compounds used as intermediates in the synthesis of a large number of products used in both the chemical and pharmaceutical industries. Of particular interest is the anti-arhythmic drug ticlopidine.
The process according to the instant invention comprises acylating a thiophene compound of the formula: ##STR3## in which R.sub.1 and R.sub.2 are as defined in formula (I); and subsequently reducing and hydrolyzing the intermediate product.
According to one embodiment of the present invention the acylation is carried out by adding a compound of the formula (11) to a mixture of an acylation catalyst such as AlCl.sub.3 and an acylating compound of the formula III or IV: ##STR4## wherein R.sub.3 is selected from the group consisting of C.sub.1-4 lower alkyl, C.sub.1-4 lower alkoxy, phenoxy, NO.sub.2, CF.sub.3, Cl, Br, I and F, and n=0 to 3.
Preferable acylating compounds for use in the present invention include formula III - hippuryl chloride and formula IV -2-phenyl-5-oxazolone (Lancaster Synthesis) wherein n=0 for each compound respectively.
It is an important feature of the present invention to premix the catalyst with the acylating compound (III or IV) prior to the addition of the thiophene compound (11) to the mixture. This premixing provides greatly improved yields in the resultant product and is the inverse of that typically taught in the literature. This is demonstrated in the following table:
______________________________________ Acylating Order of Addition AlCl.sub.3 Last Agent AlCl.sub.3 First (Inverse) (Normal) ______________________________________ Hippuryl Chloride 37.6-49.8% Yield 20.9% Yield 2-phenyl-5-oxazolone 47.3-52.1% Yield 38.8% Yield ______________________________________
The acylation catalyst is necessarily an acid catalyst, preferably a Lewis acid catalyst, such as AlCl.sub.3, SnCl.sub.4, AlBr.sub.3, BF.sub.3, and the like, all of which are capable of promoting a Friedel-Crafts type reaction.
Suitable inert solvents for conducting the acylation reaction include any solvent suitable for Friedel-Crafts reactions, for example: methylene chloride, nitromethane, carbon disulfide, nitro benzene, 1,2-dichloroethane and the like.
The acylation reaction is carried out in any suitable temperature range between the freezing and boiling points of the solvent, preferably from 0.degree. C. to room temperature.
The acylated compound produced from the reaction of compound (II) with a compound of either formula III or IV is represented by the formula: ##STR5## wherein R.sub.1, R.sub.2, R.sub.3, and n are defined above.
The preferred acylated compound (V) prepared in accordance with the instant invention is .alpha.-N-benzoylamino-2-acetylthiophene as represented by the formula (V) where R.sub.1 and R.sub.2 are hydrogen and n=0.
The intermediate product of formula (V) is subsequently reduced and hydrolyzed to produce the compounds of the instant invention, namely, 2-(2-thienyl)-ethylamine derivatives of formula (I).
Typically hydrolysis is carried out utilizing an acid having a concentration from 5 to 100% such as HCl, H.sub.2 SO.sub.4, and the like but dilute bases such as NaOH may also be employed. The hydrolysis reaction is performed at temperatures ranging from ambient to the boiling point of solvent which is preferably water. Hydrolysis of compound (V) cleaves the benzoyl group to form a resultant pendent amino group on the thienyl derivative.
The acylated product (V) is reduced by reduction of the ketone substituent utilizing a variety of reducing conditions in accordance with procedures in the following articles which represent the state-of-the-art.
__________________________________________________________________________ Conditions Reference __________________________________________________________________________ KOH/NH.sub.2 NH.sub.2 (HOCH.sub.2 CH.sub.2).sub.2 O Gooman, M. M., Kirsch, G. and Knapp, Jr., F. F. J. Med. Chem., (1984), 2, 390. See also J. Amer. Chem. Soc., (1946), 69, 2487; Organic Reaction, (1948), 378. NH.sub.2 NH.sub.2 ; then KOt--Bu/DMSO or THF Cram, D. J., Sahyun, M. R. V., and Knox, G. R., J. Amer. Chem. Soc., (1962), 84, 1734. NH.sub.2 NH.sub.2 ; then KOt--Bu/toluene Grundon, M. F. et al. J. Chem. Soc., (1963), 1855. HSCH.sub.2 CH.sub.2 SH/Ra--Ni Sobti, R. R. and Dev. S. Tetrahedron, (1970). 26, 649. TFA/NaBH.sub.4 Gribble, G. W. et al, Synthesis (1978), 763; J. Org. Chem., (1978) 43, 2299. AlCl.sub.3 /LAH Brown, B. R. and White, A. M. S., J. Chem. Soc., (1957), 3755; Blackwel, J. and Hickinbottom, W. J., J. Chem. Soc. Chem. Commun. (1969). 919. Zn/HCl(g) Yamamura, S. et al, J. Chem. Soc., Chem. Commun., (1969), 919. Zn/NH.sub.3 CuSO.sub.4 J. Org. Chem., (1970), 35, 711. Ni--Al/NaOH/H.sub.2 O Organic Reactions, (1953), 7, 263. Et.sub.3 SiH/TFA (or BR.sub.3) Tetrahedron, (1967), 23, 2235; J. Org. Chem., (1978), 43, 374. __________________________________________________________________________
Preferably, the reduction step is conducted in a non-polar, aprotic solvent such as diethyl ether, tetrahydrofuran or dioxane. Hydrogen chloride gas is preferably used as the reducing agent in the presence of zinc powder.
It is preferably but not necessary to perform the reduction of acylated compound (V) prior to the hydrolysis to restrict pyrazine formation. However, under basic conditions, e.g., a Wolff-Kischner reduction using hydrazine and an appropriate base, such as KOH, it is possible to carry out reduction and hydrolysis simultaneously. Other suitable bases include NaOH, NaH, and potassium tert-butoxide. This reaction can be conducted in polar protic or aprotic solvents as well as a polar solvents at a temperature between ambient and the boiling point of the solvent which is being utilized in the system.
The following examples illustrate, but do not limit the invention.
The following examples employed the procedures. Melting points were determined on a Buchi 510 melting point apparatus and are uncorrected. .sup.1 H and .sup.13 C NMR spectra were recorded on an IBM-Brucker AC-300 spectrometer. Mass spectra were recorded on either Finnigan MAT 212 or 4500, or Hewlett-Packard 5985 mass spectrometers. Reactions were followed using a combination of DB-5 capillary column on a Hewlett-Packard 5890 GC and TLC on silica coated glass plates eluting with methanol/chloroform mixtures, the spots being visualized by UV and iodine staining.
Chemicals were purchased from the Aldrich Chemical Company and were used without further purification. Solvents were J. T. Baker analytical grade. Methylene chloride was refluxed over calcium hydride in a dry nitrogen atmosphere and distilled prior to use. NMR internal standard (ISTD) purity determinations employed 2-methoxynaphthalene as the added standard, and involved a comparison of the peak areas of the methylene peak of the product with the methoxy peak of the standard.